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Synthesis 2009(11): 1797-1800  
DOI: 10.1055/s-0028-1088078
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Facile and Practical One-Pot Synthesis of β-Oxo Thioamides from β-Oxo Amides and Isothiocyanates

Peng Huanga, Dexuan Xiangb, Yang Zhoua, Yongjiu Liang*a, Tianhai Naa, Dewen Dong*a,b
a Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. of China
Fax: +86(431)85098966; e-Mail: dwdong@ciac.jl.cn;
b Department of Chemistry, Northeast Normal University, Changchun, 130024, P. R. of China

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Publication History

Received 24 December 2008
Publication Date:
27 April 2009 (online)

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Abstract

A facile and practical one-pot synthesis of β-oxo thio­amides from β-oxo amides has been developed. By treatment with isothiocyanates in ethanol in the presence of potassium carbonate, a series of β-oxo amides was converted, under reflux, in high yields into the corresponding β-oxo thioamides.

Key words

thioamides - 3-oxo amides - isothiocyanates - ethanol - potassium carbonate

Thioamides represent an important class of carboxylic acid derivatives with diverse bio- and pharmacological activities. [¹] [²] Over the past decades, they have found a variety of applications, for example as plant protection agents, drugs, flotation and vulcanization agents, additives to lubricating oils and greases, and ligands in coordination chemistry. They are also widely used as versatile synthons in organic synthesis, including in regio- and stereoselective heterocyclization reactions. [¹-³] So far, extensive work has generated many approaches for the synthesis of thioamides. The most common approaches involve the thionation of their amide analogues. [²a] [4] The direct thionation of amides has been extensively studied with various thionating reagents, such as phosphorus pentasulfide, diethylthiocarbamoyl chloride, boron sulfide, ethyl aluminum sulfide, and Lawesson’s reagent. [5-7] To provide mild thionation conditions, the prior activation of amides with electrophilic reagents has been investigated. [8] Recently, polymer-supported thionating reagents have been developed for the thionation of amides. [³b] [9] Thio­amides can be synthesized directly by reaction of isothiocyanates with aromatic and heteroaromatic compounds in the presence of Lewis acids, in a Friedel-Crafts-type reaction. [¹0] Other methods reported for thioamide synthesis include the use of nitriles, aldehydes or ketones, amidines, or isothiocyanates as starting materials. [²a] Nevertheless, there is still a need for novel and practical methods for the synthesis of more elaborate and functionalized thioamides to be developed.

β-Oxo thioamides make up an important subset of thio­amides, since another reactive site, that is, the β-carbonyl group, in the molecule turn them into more useful building blocks in organic synthesis. However, most of the available approaches for accessing thioamides are not general for the preparation of β-oxo thioamides. Recently, Liang and co-workers described an efficient synthetic route to β-oxo thioamides by fragmentation of the dithiolane ring of α-oxo ketene S,S-acetals. [¹¹]

During the course of our studies on the chemistry and applications of α-oxo ketene S,S-acetals, [¹²] we successfully achieved thioacetalization using α-oxo ketene S,S-acetals as odorless and efficient thiol equivalents. [¹³] We also noticed that α-acyl ketene S,S-acetals are easily deacylated under the investigated conditions. In light of these studies, we envisaged a synthetic route to thioamides by the reaction of β-oxo amides and isothiocyanates, in which an acyl group of the substrate serves as an activated group (Scheme  [¹] ). Investigating this, we developed a facile and practical one-pot synthesis of β-oxo thioamides. We wish to describe our preliminary results here.

Scheme 1 Proposed synthetic approach to β-oxo thioamides

First, the reaction of 3-oxo-N-phenylbutanamide (1a) with phenyl isothiocyanate (2a) (1.2 equiv) in N,N-di­methylformamide in the presence of potassium carbonate (2.0 equiv) was investigated (Scheme  [²] ). The reaction mixture was stirred at room temperature for five hours, and then neutralized with dilute hydrochloric acid. The precipitated yellow solid was washed with water and dried in vacuo, but was, unfortunately, found to be an inseparable mixture. Treatment of the solid with ethanol (95%) under reflux for 1.5 hours, followed by cooling to room temperature furnished a white crystalline product, which was characterized as 3-anilino-N-phenyl-3-thioxopropanamide (3aa) on the basis of its spectral and analytical data (Scheme  [²] ).

Scheme 2 Reaction of 3-oxo-N-phenylbutanamide (1a) with phenyl isothiocyanate (2a)

The results suggested that an intermediate α-oxo ketene monothiolate anion (see Scheme  [¹] ) [¹4] possibly forms during the reaction at room temperature, and that its deacylation might require a high temperature for complete conversion. This encouraged us to attempt to synthesize β-oxo thioamides from β-oxo amides in one pot. Thus, the reaction of 1a and 2a (1.2 equiv) was performed in N,N-dimethylformamide in the presence of potassium carbonate (2.0 equiv) at room temperature for one hour, followed by reaction at 80 ˚C for another hour. After workup and purification of the resulting reaction mixture, β-oxo thioamide 3aa was obtained in 92% yield (Scheme  [²] ).

Subsequently, the reaction conditions, including solvent, reaction temperature, base, and 1a/2a/base ratio were investigated with the aim to optimize the yield of β-oxo thioamide 3aa (Scheme  [²] ). It was found that the reaction of 1a and 2a also proceeded in other organic solvents, such as dimethyl sulfoxide, ethanol, butanone, and tetrahydrofuran. The reaction was significantly accelerated by an increase of the reaction temperature. The use of a strong base, such as sodium hydroxide, shortens the reaction time, but at the same time results in lower product yield and the formation of byproducts. Longer reaction time accompanied by lower conversion resulted when the reaction was performed in the presence of weak organic bases, such as triethylamine. A series of experiments revealed that potassium carbonate and ethanol were the best base and solvent, respectively, among those tested, and that the optimal results were obtained when the reaction of 1a and 2a (1.0 equiv) was carried in the presence of 1.2 equivalents of potassium carbonate in ethanol under reflux for 1.5 hours; this gave 3aa in 94% yield (Table  [¹] , entry 1). In this case, the resulting reaction mixture was cooled to room temperature, neutralized with dilute hydrochloric acid, and the precipitated solid was filtered, washed with water, and dried in vacuo to furnish pure product 3aa; thus, the thioamide synthesis was followed by a very simple, nonchromatographic separation process. It should be mentioned that a similar approach to β-oxo thioamide 3aa was previously reported by Barnikow: the reaction was carried with a diarylmalonamide and an isothiocyanate with the aid of sodium alkoxide. [¹4a]

Table 1 One-Pot Synthesis of β-Oxo Thioamides from β-Oxo Amides 1 and Isothiocyanates 2

Entry 1 R¹ 2 R² 3 Timea (h) Yieldb
(%)
 1 1a Ph 2a Ph 3aa 1.5 94
 2 1b 4-ClC6H4 2a Ph 3ba 1.7 96
 3 1c 4-MeOC6H4 2a Ph 3ca 1.8 93
 4 1d 4-MeC6H4 2a Ph 3da 1.5 92
 5 1e 2-ClC6H4 2a Ph 3ea 1.6 95
 6 1f 2-MeOC6H4 2a Ph 3fa 1.6 93
 7 1g 2-MeC6H4 2a Ph 3ga 1.5 94
 8 1h 2,4-Me2C6H3 2a Ph 3ha 1.7 90
 9 2i 2-MeO-5-ClC6H3 2a Ph 3ia 1.8 89
10 1j Me 2a Ph 3ja 2.0 90
11 1a Ph 2b Bn 3ab 2.5 81
12 1b 4-ClC6H4 2b Bn 3bb 2.2 83
13 1c 4-MeOC6H4 2b Bn 3cb 2.1 77
14 1d 4-MeC6H4 2b Bn 3db 2.0 78
a Reaction time under reflux.
b Isolated yields.

Having established the optimal conditions for the synthesis of β-oxo thioamide 3aa, we investigated the scope of the reaction with regard to other R¹ and R² groups in starting materials 1 and 2 (Table  [¹] ). The results of the reactions of other β-oxo amides 1b-j with isothiocyanates 2a and 2b (1.0 equiv) in ethanol in the presence of potassium carbonate (1.2 equiv) under reflux are summarized in Table  [¹] . [¹5] The reactions of β-oxo amides 1b-j bearing various aryl- and alkylamide groups with phenyl isothiocyanate (2a) proceeded smoothly, affording the corresponding β-oxo thioamides 3ba-3ja in excellent yields (Table  [¹] , entries 2-10). The versatility of this facile β-oxo thioamide synthesis was demonstrated by the reactions of β-oxo amides 1a-d with benzyl isothiocyanate (2b) under identical reaction conditions (Table  [¹] , entries 11-14). It is worth noting that, in all cases, pure products 3 could be obtained by nonchromatographic separation. If necessary, the products can be further purified by recrystallization from ethanol-water (1:1) or flash chromatography (silica gel, Et2O-PE, 3:2). However, we were unable to obtain the corresponding β-oxo thioamides when acetylacetone or ethyl 3-oxobutanoate were subjected to the identical conditions that were used for β-oxo amides 1; this might be due to the instability of the intermediate α-oxo ketene monothiolate anions. [¹5]

In summary, we have described a facile and practical one-pot synthesis of β-oxo thioamides by the reactions of β-oxo amides with isothiocyanates in ethanol in the presence of potassium carbonate under reflux. The simple exe­cution and separation, the use of commercially available substrates, the mild conditions, high yields, and wide range of synthetic potential of the products make this protocol very attractive for use in academic research and practical applications.

All melting points were determined in open capillary tubes in a Thiele apparatus and are uncorrected. IR spectra were recorded on a Magna-560 infrared spectrometer of samples prepared on KBr plates as neat films. NMR spectra of samples in CDCl3 (unless stated otherwise) were recorded on a Varian Inova-500 spectrometer. Elemental analyses were carried out on a Perkin-Elmer PE-2400 analyzer. Starting materials and solvents were obtained from commercial sources and used without treatment.

3-Anilino- N -phenyl-3-thioxopropanamide (3aa); [¹4] Typical Procedure

A 50-mL round-bottomed flask was charged with K2CO3 (0.83 g, 6.0 mmol), 3-oxo-N-phenylbutanamide (1a; 0.89 g, 5.0 mmol) and EtOH (15 mL) at r.t. After the reaction mixture had stirred at r.t. for 0.5 h, PhNCS (2a; 0.68 g, 5.0 mmol) was added dropwise within 10 min. The mixture was heated and stirred under reflux for 1.5 h until complete conversion had taken place, as indicated by TLC. Then the resulting mixture was cooled to r.t. and neutralized with dilute aq HCl. The precipitated solid was collected by filtration, washed with H2O, and dried in vacuo; this furnished pure product 3aa.

Yield: 1.27 g (94%); white solid; mp 147-149 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 4.10 (s, 2 H), 7.17 (t, J = 7 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.34 (t, J = 8 Hz, 2 H), 7.41 (t, J = 8 Hz, 2 H), 7.54 (d, J = 7.5 Hz, 2 H), 7.79 (d, J = 7.5 Hz, 2 H), 8.86 (s, 1 H), 11.33 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 54.6, 120.5, 123.6, 125.2, 127.2, 128.9, 129.1, 137.0, 138.4, 166.5, 193.9.

Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C, 66.48; H, 5.17; N, 10.48.

3-Anilino- N -(4-chlorophenyl)-3-thioxopropanamide (3ba)

White solid; mp 158-160 ˚C.

IR (neat): 3246, 3183, 3106, 2951, 1680, 1603, 1541, 1492, 1430, 1398, 826, 735, 686 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 4.07 (s, 2 H), 7.29-7.31 (m, 3 H), 7.41 (t, J = 8 Hz, 2 H), 7.48 (d, J = 7 Hz, 2 H), 7.75 (d, J = 8 Hz, 2 H), 8.72 (s, 1 H), 11.02 (s, 1 H).

¹³C NMR (125 MHz, DMSO-d 6): δ = 55.4, 121.2, 123.4, 126.7, 127.6, 129.1, 129.2, 138.4, 139.9, 166.3, 194.9.

Anal. Calcd for C15H13ClN2OS: C, 59.11; H, 4.30; N, 9.19. Found: C, 59.34; H, 4.13; N, 9.12.

3-Anilino- N -(4-methoxyphenyl)-3-thioxopropanamide (3ca)

White solid; mp 131-132 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 3.81 (s, 3 H), 4.03 (s, 2 H), 6.89 (d, J = 8 Hz, 2 H), 7.42 (d, 5 H), 7.79 (s, 2 H), 8.43 (s, 1 H), 11.33 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 54.3, 55.5, 114.1, 122.4, 123.5, 127.1, 128.8, 129.9, 138.5, 157.0, 166.4, 193.9.

Anal. Calcd for C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33. Found: C, 63.79; H, 5.42; N, 9.46.

3-Anilino-3-thioxo- N -4-tolylpropanamide (3da) [¹4a]

White solid; mp 157-159 ˚C.

IR (neat): 3243, 3189, 3111, 3025, 2918, 1677, 1598, 1540, 1511, 1492, 1434, 815, 760, 711 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3 H), 4.02 (s, 2 H), 7.11 (d, J = 8.5 Hz, 2 H), 7.24 (t, J = 7 Hz, 1 H), 7.37 (t, J = 8.5 Hz, 4 H), 7.75 (d, J = 8 Hz, 2 H), 8.35 (s, 1 H), 11.13 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 21.0, 54.4, 120.6, 123.6, 127.1, 128.8, 129.5, 134.3, 135.0, 138.5, 166.3, 193.9.

Anal. Calcd for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85. Found: C, 67.45; H, 5.81; N, 9.73.

3-Anilino- N -(2-chlorophenyl)-3-thioxopropanamide (3ea)

White solid; mp 151-152 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 4.13 (s, 2 H), 7.11 (t, J = 7.5 Hz, 1 H), 7.29 (d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7 Hz, 3 H), 7.79 (d, J = 8 Hz, 2 H), 8.22 (d, J = 6.5 Hz, 1 H), 8.80 (s, 1 H), 11.08 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 55.6, 122.6, 123.4, 124.7, 125.9, 127.1, 127.5, 128.9, 129.5, 133.7, 138.6, 166.6, 193.2.

Anal. Calcd for C15H13ClN2OS: C, 59.11; H, 4.30; N, 9.19. Found: C, 59.36; H, 4.23; N, 9.08

3-Anilino- N -(2-methoxyphenyl)-3-thioxopropanamide (3fa)

White solid; mp 138-140 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 3.91 (s, 3 H), 4.06 (s, 2 H), 6.92 (d, J = 8 Hz, 1 H), 6.98 (t, J = 8 Hz, 1 H), 7.12 (t, J = 8 Hz, 1 H), 7.28 (s, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.81 (d, J = 8 Hz, 2 H), 8.28 (d, J = 8.5 Hz, 1 H), 8.39 (s, 1 H), 11.37 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 55.0, 55.8, 110.3, 120.3, 120.8, 123.4, 125.0, 126.6, 126.9, 128.8, 138.7, 148.6, 166.4, 193.3.

Anal. Calcd for C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33. Found: C, 64.13; H, 5.44; N, 9.37.

3-Anilino-3-thioxo- N -2-tolylpropanamide (3ga)

White solid; mp 124-125 ˚C.

IR (neat): 3285, 3217, 3147, 3108, 1674, 1600, 1537, 1498, 1415, 811, 753, 684 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3 H), 4.14 (s, 2 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.17 (d, J = 7 Hz, 1 H), 7.21 (d, J = 8 Hz, 1 H), 7.28 (d, J = 7 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.73 (d, J = 8 Hz, 1 H), 7.78 (d, J = 8 Hz, 2 H), 8.70 (s, 1 H), 11.31 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 18.2, 55.4, 123.3, 123.4, 126.1, 126.5, 127.1, 128.8, 130.5, 130.8, 134.9, 138.6, 166.5, 194.1.

Anal. Calcd for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85. Found: C, 67.74; H, 5.62; N, 9.94.

3-Anilino- N -(2,4-dimethylphenyl)-3-thioxopropanamide (3ha)

White solid; mp 116-117 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 2.25 (s, 3 H), 2.30 (s, 3 H), 4.09 (s, 2 H), 7.00 (t, J = 9 Hz, 2 H), 7.39 (t, J = 7.5 Hz, 2 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.76-7.78 (m, 3 H), 8.36 (s, 1 H), 11.33 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 18.1, 20.9, 55.1, 123.3, 123.7, 127.0, 127.1, 128.8, 130.8, 131.4, 132.2, 135.9, 138.7, 166.6, 194.1.

Anal. Calcd for C17H18N2OS: C, 68.42; H, 6.08; N, 9.39. Found: C, 68.58; H, 6.11; N, 9.45.

3-Anilino- N -(5-chloro-2-methoxyphenyl)-3-thioxopropan­amide (3ia)

White solid; mp 152-153 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 3.90 (s, 3 H), 4.06 (s, 2 H), 6.82 (d, J = 9 Hz, 1 H), 7.07 (q, J = 8.5, 2.5 Hz, 1 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.80 (d, J = 7.5 Hz, 2 H), 8.37 (s, 1 H), 8.53 (s, 1 H), 11.18 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 55.2, 56.1, 111.1, 120.1, 123.4, 124.3, 125.8, 127.0, 127.5, 128.9, 138.6, 147.2, 166.4, 193.1.

Anal. Calcd for C16H15ClN2O2S: C, 57.40; H, 4.52; N, 8.37. Found: C, 57.23; H, 4.43; N, 8.51.

3-Anilino- N -methyl-3-thioxopropanamide (3ja)

White solid; mp 118-120 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 2.85 (d, 3 H), 3.88 (s, 2 H), 6.73 (s, 1 H), 7.26 (t, J = 7.5 Hz, 1 H), 7.39 (t, J = 8 Hz, 2 H), 7.79 (d, J = 8 Hz, 2 H), 11.60 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 26.7, 53.5, 123.4, 127.0, 128.9, 138.8, 169.1, 194.1.

Anal. Calcd for C10H12N2OS: C, 57.67; H, 5.81; N, 13.45. Found: C, 57.49; H, 5.90; N, 13.21.

3-(Benzylamino)- N -phenyl-3-thioxopropanamide (3ab)

White solid; mp 176-177 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 3.87 (s, 2 H), 4.84 (d, J = 5.5 Hz, 2 H), 7.27-7.44 (m, 10 H), 8.70 (s, 1 H), 9.23 (s, 1 H).

¹³C NMR (125 MHz, DMSO-d 6): δ = 49.2, 53.4, 121.2, 127.5, 127.8, 128.2, 128.9, 129.2, 137.4, 138.4, 166.3, 196.0.

Anal. Calcd for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85. Found: C, 67.34; H, 5.72; N, 9.68

3-(Benzylamino)- N -(4-chlorophenyl)-3-thioxopropanamide (3bb)

White solid; mp 170-171 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 3.87 (s, 2 H), 4.84 (d, J = 5.5 Hz, 2 H), 7.28 (d, J = 8.5 Hz, 2 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.37 (d, J = 7 Hz, 4 H), 7.43 (d, J = 9 Hz, 2 H), 8.71 (s, 1 H), 9.23 (s, 1 H).

¹³C NMR (125 MHz, DMSO-d 6): δ = 49.2, 53.5, 121.2, 127.5, 127.8, 128.2, 128.9, 129.2, 137.4, 138.4, 166.3, 196.0.

Anal. Calcd for C16H15ClN2OS: C, 60.28; H, 4.74; N, 8.79. Found: C, 60.63; H, 4.61; N, 8.91.

3-(Benzylamino)- N -(4-methoxyphenyl)-3-thioxopropanamide (3cb)

White solid; mp 148-149 ˚C.

IR (neat): 3233, 3189, 3126, 3063, 2965, 1662, 1608, 1538, 1510, 1406, 1249, 1172, 1112, 1030, 828, 750, 698 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 3.79 (s, 3 H), 3.87 (s, 2 H), 4.85 (d, J = 5 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 7.34-7.37 (m, 7 H), 8.21 (s, 1 H), 9.48 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 50.4, 52.8, 55.4, 114.1, 122.2, 128.0, 128.2, 128.8, 130.1, 135.6, 156.9, 165.8, 195.1.

Anal. Calcd for C17H18N2O2S: C, 64.94; H, 5.77; N, 8.91. Found: C, 65.23; H, 5.65; N, 8.84.

3-(Benzylamino)-3-thioxo- N -4-tolylpropanamide (3db)

White solid; mp 163-164 ˚C.

¹H NMR (500 MHz, CDCl3): δ = 2.32 (s, 3 H), 3.87 (s, 2 H), 4.85 (d, J = 5 Hz, 2 H), 7.13 (d, J = 8 Hz, 2 H), 7.34-7.37 (m, 7 H), 8.15 (s, 1 H), 9.36 (s, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 20.9, 50.4, 52.9, 120.4, 128.0, 128.3, 128.8, 129.5, 134.4, 134.7, 135.6, 165.8, 195.0.

Anal. Calcd for C17H18N2OS: C, 68.42; H, 6.08; N, 9.39. Found: C, 68.28; H, 6.12; N, 9.47.

Acknowledgment

Financial support of this research by the National Natural Science Foundation of China (20572013 and 20872136), the Ministry of Education of China (105061), and the Department of Science and Technology of Jilin Province (20050309) is gratefully acknowledged.

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Scheme 1 Proposed synthetic approach to β-oxo thioamides

Scheme 2 Reaction of 3-oxo-N-phenylbutanamide (1a) with phenyl isothiocyanate (2a)